Background: The Repeat Expansion Diseases are caused by the intergenerational expansion of a specific tandem repeat. Expansion of a CGGCCG-repeat in the 5' UTR of the FMR1 gene is associated with 3 different clinical presentations: Individuals with 60-200 repeats, so-called premutation alleles, are at risk for Fragile X-associated tremor-ataxia syndrome (FXTAS). In addition to symptoms resulting from cerebellar degeneration, individuals with FXTAS can have a late-onset dementia as well as bowel and urinary incontinence. Female carriers of premutation alleles are also at risk of premature ovarian failure. Since the carrier frequency of these alleles is 1/250 these may be significant public health issues. In addition to these problems, the premutation allele can undergo further expansion on maternal transfer resulting in alleles with >200 repeats. Individuals who inherit these so-called full mutation alleles almost always have Fragile X mental retardation syndrome (FXS), the most common cause of mental retardation and the most common known cause of autism. Hyperphagia, digestive difficulties and obesity are frequent comorbid features and a subset of individuals with FXS have symptoms that overlap with those seen in Prader-Willi syndrome. Anxiety and depression are also common.[unreadable] [unreadable] Progress report: We have generated FXS premutation mice containing 120 CGG.CCG-repeats in the 5 UTR of the endogenous murine Fmr1 gene (Entezam et. al., 2007). Like humans with the same number of repeats, these mice produce elevated levels of Fmr1 mRNA that recent data, from my group (Handa, Saha and Usdin, 2003) and elsewhere, suggests is toxic. These mice also show pathological changes including the accumulation of ubiquitin and lamin A/C positive intranuclear neuronal inclusions in brain. These pathological changes are reminiscent of those seen in human carriers of premutation alleles and suggest that these animals will be suitable for studying the repeat-mediated RNA pathology thought to be responsible for FXTAS. These mice also show evidence of abnormalities in follicular recruitment and ovarian histopathology that suggest they may also be good models for the premature ovarian pathology seen in female carriers of premutation alleles. [unreadable] [unreadable] Parallels with myotonic dystrophy, another repeat expansion disorder, have lead to the suggestion that the CGG-repeats in the transcripts from premutation alleles may sequester important proteins that ultimately affect cerebellar or ovarian function. Using a variety of approaches we have identified a number of proteins from mouse brain that interact with CGG-RNA repeats. Some of these proteins have properties that suggest a role in the pathology seen in premutation carriers. Further characterization of these proteins and their contribution to FXTAS is currently underway.[unreadable] [unreadable] These mice also have clear regional deficiencies in the Fmr1 gene product, FMRP, in the brain and ovary. This is thought to be related to difficulties translating RNAs with large CGG-repeat tracts due to the formation of stable RNA hairpins (Handa, Saha and Usdin, 2003). Preliminary results from behavioral studies in our mice show specific learning defects consistent with the regional FMRP deficits. While a inverse relationship between repeat number and FMRP levels has been seen in human lymphocytes, the etiology of behavioral and cognitive problems in human premutation carriers has been controversial. Our data suggest that repeat-mediated effects on FMRP translation may be responsible for some of the symptoms seen in premutation carriers.